EP3566714A1 - Influenza virus vaccines and uses thereof - Google Patents

Influenza virus vaccines and uses thereof Download PDF

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Publication number
EP3566714A1
EP3566714A1 EP19175392.0A EP19175392A EP3566714A1 EP 3566714 A1 EP3566714 A1 EP 3566714A1 EP 19175392 A EP19175392 A EP 19175392A EP 3566714 A1 EP3566714 A1 EP 3566714A1
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Prior art keywords
seq
amino acid
polypeptides
sequence
influenza
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German (de)
English (en)
French (fr)
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Jan Willem Meijberg
Antonietta IMPAGLIAZZO
Ronald Vogels
Robert Heinz Edward Friesen
Philippe ALARD
Stefan Loverix
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Janssen Vaccines and Prevention BV
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Janssen Vaccines and Prevention BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5258—Virus-like particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand
    • C07K2319/21—Fusion polypeptide containing a tag with affinity for a non-protein ligand containing a His-tag
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/35—Fusion polypeptide containing a fusion for enhanced stability/folding during expression, e.g. fusions with chaperones or thioredoxin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/50—Fusion polypeptide containing protease site
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/73—Fusion polypeptide containing domain for protein-protein interaction containing coiled-coiled motif (leucine zippers)
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16151—Methods of production or purification of viral material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16171—Demonstrated in vivo effect

Definitions

  • polypeptides of the invention comprise one or more mutations in the HA2 amino acid sequence connecting the C-terminal residue of helix A to the N-terminal residue of helix CD, as indicated in FIG. 1 .
  • one or more hydrophobic amino acids in said HA2 amino acid sequence have been substituted by hydrophilic amino acids, such as polar and/or charged amino acids, or the flexible amino acid glycine (G).
  • Constant substitution refers to replacement of an amino acid of one class is with another amino acid of the same class.
  • a conservative substitution does not alter the structure or function, or both, of a polypeptide.
  • Classes of amino acids for the purposes of conservative substitution include hydrophobic (e.g. Met, Ala, Val, Leu), neutral hydrophilic (e.g. Cys, Ser, Thr), acidic (e.g. Asp, Glu), basic (e.g. Asn, Gln, His, Lys, Arg), conformation disrupters (e.g. Gly, Pro) and aromatic (e.g. Trp, Tyr, Phe).
  • influenza virus subtype refers to influenza A virus variants that are characterized by combinations of the hemagglutinin (H) and neuramidase (N) viral surface proteins.
  • influenza virus subtypes may be referred to by their H number, such as for example "influenza virus comprising HA of the H3 subtype", “influenza virus of the H3 subtype” or “H3 influenza”, or by a combination of a H number and an N number, such as for example "influenza virus subtype H3N2" or "H3N2".
  • Non-human strains also include the host of origin in the nomenclature.
  • the influenza A virus subtypes can further be classified by reference to their phylogenetic group.
  • Phylogenetic analysis has demonstrated a subdivision of hemagglutinins into two main groups: inter alia the H1, H2, H5 and H9 subtypes in phylogenetic group 1 ("group 1" influenza viruses) and inter alia the H3, H4, H7 and H10 subtypes in phylogenetic group 2 (“group 2" influenza viruses).
  • Stem domain polypeptide refers to a polypeptide that comprises one or more polypeptide chains that make up a stem domain of a naturally-occurring (or wild-type) hemagglutinin (HA).
  • a stem domain polypeptide is a single polypeptide chain (i.e. corresponding to the stem domain of a hemagglutinin HA0 polypeptide) or two polypeptide chains (i.e. corresponding to the stem domain of a hemagglutinin HA1 polypeptide in association with a hemagglutinin HA2 polypeptide).
  • the polypeptides do not comprise the signal sequence.
  • the skilled person will be able to prepare the polypeptides described herein without the signal peptides (e.g. amino acids 1-17 of SEQ ID NO: 1).
  • the polypeptides of the invention contain the intracellular sequences of HA and the transmembrane domain. In other embodiments, the polypeptides of the invention do not comprise the intracellular sequences of HA and the transmembrane domain.
  • influenza hemagglutinin stem domain polypeptides may be based on HA of any naturally occurring influenza A hemagglutinin virus of a subtype that is used in human influenza vaccines.
  • Influenza A virus subtypes that are generally used in influenza vaccines are influenza A viruses of the H1, H3 or H5 subtypes.
  • x is 53 and y is 303.
  • the HA1 domain comprises the mutations L58T, V314T, and I316T
  • the HA2 domain comprises one or more of the following mutations: F406S, V409T, and L416S.
  • the polypeptides selectively bind to the antibodies CR6261 and/or CR9114. In an embodiment, the polypeptide does not bind to the antibody CR8057.
  • CR6261 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 20 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21;
  • CR9114 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 18 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.
  • CR8057 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23.
  • Applicants have previously identified broadly neutralizing antibodies isolated from primary human B-cells from vaccinated individuals some of which were specific for group 1 (e.g. CR6261, as described in WO 2008/028946 ) and some of which were specific for group 2 influenza viruses (e.g. CR8020 as described in WO 2010/130636 ). Detailed analysis of the epitopes of these monoclonal antibodies has revealed the reason for the lack of cross-reactivity of these specific antibodies. In both cases the presence of glycans in group 1 or group 2 HA molecules on different positions at least partly explained the fact that the antibodies are group-specific.
  • the amino acid sequence connecting the C-terminal residue of helix A to the N-terminal residue of helix CD corresponds to the amino acid sequence between the amino acid on position 400 and the amino acid on position 420 of HA2 of SEQ ID NO: 89, or the amino acid residues on equivalent positions in other H3 virus strains, wherein the polypeptides comprise one or more mutations in the amino acid sequence connecting the C-terminal residue of helix A to the N-terminal residue of helix CD, i.e. the amino acid sequence spanning from amino acid 400-420 of SEQ ID NO: 89, or equivalent amino acid residues in other H3 influenza virus strains.
  • the cleavage site between HA1 and HA2 has been removed.
  • the removal of the cleavage site at position 345 (numbering refers to SEQ ID NO: 89) has been mutated (R345Q) to prevent the formation of HA1 and HA2 from HA0.
  • residue 347 to 351 (IFGAI, part of the fusion peptide) can additionally be deleted to minimize the exposure of hydrophobic residues to the aqueous solvent.
  • the positive charge at the cleavage is 100% conserved in H3 and this mutation can therefore be applied in all sequences.
  • Engineered disulfide bridges are created by mutating at least one (if the other is already a cysteine), but usually two residues that are spatially close into cysteine, that will spontaneously or by active oxidation form a covalent bond between the sulfur atoms of these residues.
  • An alternative cysteine bridge can be created between (the equivalent of) position 334 and 393 in H3 A/Wisconsin/67/2005 (SEQ ID NO: 89) by mutation of these residues into cysteine.
  • the cysteine at (the equivalent of) position 321 is modified into a glycine to avoid formation of unwanted disulfide bridges.
  • Promoters can be constitutive or regulated, and can be obtained from various sources, including viruses, prokaryotic, or eukaryotic sources, or artificially designed. Expression of nucleic acids of interest may be from the natural promoter or derivative thereof or from an entirely heterologous promoter (Kaufman, 2000). Some well-known and much used promoters for expression in eukaryotic cells comprise promoters derived from viruses, such as adenovirus, e.g.
  • the polypeptides, nucleic acids and/or immunogenic compositions may be administered to a subject in combination with one or more other active agents, such as existing, or future influenza vaccines, monoclonal antibodies and/or antiviral agents, and/or antibacterial, and/or immunomodulatory agents.
  • the one or more other active agents may be beneficial in the treatment and/or prevention of an influenza virus disease or may ameliorate a symptom or condition associated with an influenza virus disease.
  • the one or more other active agents are pain relievers, anti-fever medications, or therapies that alleviate or assist with breathing.
  • full-length recombinant influenza A subtypes H1 (A/New Caledonia/20/1999), H3 (A/Wisonsin/67/2005) and H7 (A/Netherlands/219/2003) HAs were expressed on the surface of PER.C6 cells.
  • SC09-114 was shown to specifically bind to influenza A subtypes H1, H3 and H7 HA.
  • Heavy and light chain variable regions of the scFv were cloned as described before ( WO 2008/028946 ).
  • the resulting expression constructs encoding the human IgG1 heavy and light chains were transiently expressed in combination in 293T cells and supernatants containing the human IgG1 antibody CR9114 were obtained and produced using standard purification procedures.
  • the amino acid sequence of the CDRs of the heavy and light chains of CR9114 are given in Table 1.
  • the nucleotide and amino acid sequences and of the heavy and light chain variable regions are given below.
  • PER.C6 cells full-length recombinant influenza A subtypes H1 (A/New Caledonia/20/1999), H3 (A/Wisonsin/67/2005) and H7 (A/Netherlands/219/2003) HAs were expressed on the surface of PER.C6 cells.
  • the cells were incubated with CR9114 for 1 hr followed by three wash steps with PBS+0.1%BSA. Bound antibody was detected using PE conjugated anti-human antibody.
  • untransfected PER.C6 cells were used as CR9114 showed cross-binding activity to influenza A subtypes H1, H3 and H7 HA but not wild-type PER.C6 cells. See Table 2.
  • the polypeptides of the invention contain the intracellular sequences of HA and the transmembrane domain.
  • the cytoplasmic sequence and the transmembrane sequence from position (or the equivalent thereof) 523, 524, 525, 526, 526, 527, 528, 529, or 530 of HA2 to the C-terminus of HA2 were removed so that a secreted (soluble) polypeptide was produced following expression in cells, which can be used e.g. in a vaccine.
  • the soluble polypeptide was further stabilized by introducing a sequence known to form trimeric structures, i.e.
  • the cM2-specific serum recognizes cM2, but none of the full-length HA or stem domain polypeptides as evidenced by the % positive cells and MFI.
  • the full length HA-specific serum stains cells expressing the corresponding full length HA (SEQ ID NO: 1), but also miniHA-clusterl (SEQ ID NO: 3), miniHA-cluster1+2 (SEQ ID NO:4) and miniHA-cluster1+4(SEQ ID NO:6), albeit at a lower level (ca 40% positive cells versus ca 80% for full length, MFI ca 1000 versus ca 7000 for full length).
  • a sequence representing a polypeptide of the invention was constructed analogously as described by Steel and coworkers (Steel et al 2010) using HA from H3 A/Wisconsin/67/2005 as the parental sequence (SEQ ID NO: 89).
  • the head of HA is removed by deletion of a part of HA1 from amino acid D69 to amino acid K292 .
  • the preparations of the polypeptides of the invention were inhomogeneous in size as determined from the SDS-PAGE and Western blot results. We hypothesized that the variation is due to variation in protein glycosylation patterns between individual protein molecules. To confirm this, small aliquots of the protein preparations were treated with 3 units of N-glycosidase F (an enzyme that removes N-linked carbohydrate moieties from Asparagine residues) for 18h at 37 °C and analyzed by SDS-PAGE and Western Blot. The results ( Figure 13a and 13b ) show that treatment with the N-glycosidase focuses the diffuse bands of the polypeptides of the invention to a single band at the expected molecular weight calculated from the amino acid sequence. This is clear evidence that the observed size inhomogeneity indeed arises from variation in glycosylation patterns.
  • N-glycosidase F an enzyme that removes N-linked carbohydrate moieties from Asparagine residues
  • the second modification is the removal of the head domain by deleting a large part of the HA1 sequence and reconnecting the N- and C-terminal sequences through a short linker.
  • the deletion can vary in length, but it is preferred that the last residue of the N-terminal sequence of HA1 and the first residue of the C-terminal sequence are spatially close together to avoid introducing strain through the linking sequence.
  • deletions can be introduced at (the equivalent positions of) P51-I336 (m2; SEQ ID NO: 133) in B/Florida/4/2006 (SEQ ID NO:132). Equivalent positions can be easily determined by those skilled in the art by aligning the sequences using a suitable algorithm such as e.g. Clustal or Muscle.
  • the native HA exists as a trimer on the cell surface. Most of the interactions between the individual monomers that keep the trimer together are located in the head domain. After removal of the head the tertiary structure is thus destabilized and therefore reinforcing the interactions between the monomers in the truncated molecule will increase the stability.
  • trimerization is mediated by the formation of a trimeric coiled coil motif. By strengthening this motif a more stable trimer can be created.
  • Sequences supporting the formation of a trimeric coiled coil derived from GCN4 are introduced at (the equivalent of) position 437 to 453 RRMKQIEDKIEEILSKI (SEQ ID NO: 135), or alternatively RMKQIEDKIEEILSKI at position 437 to 452 (SEQ ID NO: 136).

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EP19175392.0A 2011-11-28 2012-11-27 Influenza virus vaccines and uses thereof Withdrawn EP3566714A1 (en)

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US201161564086P 2011-11-28 2011-11-28
US201161564198P 2011-11-28 2011-11-28
EP11191003 2011-11-28
EP11191009 2011-11-28
EP12166268 2012-05-01
US201261720281P 2012-10-30 2012-10-30
EP12791759.9A EP2785372B1 (en) 2011-11-28 2012-11-27 Influenza virus vaccines and uses thereof
PCT/EP2012/073706 WO2013079473A1 (en) 2011-11-28 2012-11-27 Influenza virus vaccines and uses thereof

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WO2010117786A1 (en) 2009-03-30 2010-10-14 Mount Sinai School Of Medicine Of New York University Influenza virus vaccines and uses thereof
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